Osteosarcoma (OS) is an aggressive bone cancer that primarily affects children and adolescents. Standard OS treatment includes pre- and post-operative chemotherapy and aggressive surgical resection. Nonetheless, approximately 30% of patients with localized disease and 80% of patients with metastatic disease at diagnosis will fail therapy and die due to tumor progression or relapse. The main reason for treatment failure is the development of tumor therapy resistance. Clearly, it is important to identify the molecular basis for therapy resistance in OS, and ways to target therapy resistant cells. Cisplatin (CP) has been a mainstay OS therapy agent for over 30 yrs, though mechanisms for resistance to CP remain ill-defined. We established Cisplatin (CP) resistant clones from OS cells and compared them with sensitive counterparts. P53 was induced to a lower level and less active after CP in resistant clones. Resistant clones also displayed a heightened DNA damage response after CP treatment that included DNA repair and heightened/prolonged activation of the ATM-ATR-CHK1/2 damage response pathways. Importantly, we determined that small molecule MDM2 antagonists that activate p53 and p73 and which are currently in clinical development (Nutlin-3, MI-319) could effectively kill the CP resistant OS clones. Moreover, we observed that a small molecule Chk1 inhibitor (UCN01) could sensitize multiple resistant OS cell lines and selected clones to CP. Based on these findings, we hypothesize 1) that CP resistance in OS will associate with lower levels/activation of p53 or p73, a heightened DNA damage response, and DNA repair, and 2) that MDM2 antagonists and/or Chk1 inhibitors will effectively target CP resistant OS, and will block tumor regrowth in a novel animal model of human OS tumor recurrence.